CN105968109B - A kind of method for preparing Pa Boxini intermediates - Google Patents
A kind of method for preparing Pa Boxini intermediates Download PDFInfo
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- CN105968109B CN105968109B CN201610320997.8A CN201610320997A CN105968109B CN 105968109 B CN105968109 B CN 105968109B CN 201610320997 A CN201610320997 A CN 201610320997A CN 105968109 B CN105968109 B CN 105968109B
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- pyrimidine
- methyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of method for preparing Pa Boxini intermediates, this method comprises the following steps：1) by the bromopyridine of 5 methyl of compound N cyclopenta, 2 chlorine 6 shown in formula (I) simultaneously [2,3 d] (8H) ketone of pyrimidine 7 reacts the ethynyl pyridine of 5 methyl of compound N cyclopenta, 2 chlorine 6 shown in generation formula (II) simultaneously [2,3 d] pyrimidine 7 (8H) ketone in the presence of the cuprous bromide and potassium tert-butoxide with trimethylsilanylethyn；2) ethynyl pyridine of 5 methyl of compound N cyclopenta, 2 chlorine 6 shown in the formula (II) obtained step 1) simultaneously [2; 3 d] (8H) ketone of pyrimidine 7 obtains the acetylpyridine of 2 chlorine of Pa Boxini intermediate N 5 methyl of cyclopenta 6 simultaneously [2,3 d] pyrimidine 7 (8H) ketone in acidic aqueous solution reclaimed water solution；
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of method for preparing Pa Boxini intermediates.
Background technology
Pa Boxini (Palbociclib), it is a kind of cell cycle dependent kinase (CDK4/ developed by Pfizer
6) inhibitor, for negative (HER2-) advanced breast cancer of estrogen receptor positive (ER+) and human epidermal growth factor receptor 2
First-line treatment.Pa Boxini chemical entitled 6- acetyl group -8- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridines
Base] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one, concrete structure is as follows：
WO2008032157 discloses a kind of Pa Boxini synthetic method, and this method is with the chloro- 5- bromines of 2,4- bis- and ring penta
Base amine is that initiation material obtains target product by seven steps, and specific synthetic route is as follows：
The synthetic method route is grown, wherein the reaction of the 5th step has Cl and Br competitive reaction, yield is not high and purifies tired
Difficulty, also and its strictly, in addition, Heck reacts this method twice, the use of precious metal palladium catalyst is also big for reaction condition requirement
Improve production cost greatly.
CN104447743B discloses a kind of Pa Boxini preparation method, and this method is with 2- acetyl group -2- butenoic acid first
Ester and malononitrile make initiation material, through cyclization, with Cyclopentane halide necleophilic reaction then with N- [5- (1- piperazinyls) -2- pyridines
Base] guanidine condensation, dehydrogenation reaction then occurs in the presence of sodium selenate Pa Boxini is made.Although this method is preparation Pa Boxini
Provide new approach, but the overall yield of this method or relatively low, this is mainly due to the 3rd step and N- [5- (1- piperazines
Base) -2- pyridine radicals] yield is relatively low for guanidine condensation, reaction time length, and this method dehydrogenation reaction has used hypertoxic sodium selenate in addition, no
Preferably mass produce, and be unfavorable for the health of labourer.
Therefore, this area needs a kind of method for preparing Pa Boxini of simple, mild condition and high income badly.
The content of the invention
A kind of the defects of it is an object of the invention to overcome above-mentioned prior art, there is provided new preparation Pa Boxini intermediates
Method, this method is simple, mild condition, and yield is higher, is particularly suitable for industrial-scale production.
The present inventor has found under study for action, in Pa Boxini preparation process, can use and trimethyl silicane
Alkyl acetylene molecule connects alkynyl, then obtains acetyl group by the method for hydrolysis, and this method avoid use precious metal and bar
The harsh heck of part reacts and using toxic reagent catalytic dehydrogenation etc., mild condition, overall yield is higher, it also avoid simultaneously
The residual of heavy metal in the product, so as to complete the present invention.
To achieve these goals, the present invention provides a kind of method for preparing Pa Boxini intermediates, this method include with
Lower step：
1) by the compound N shown in formula (I)-chloro- 6- bromopyridines of cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7
(8H) -one reacts the compound shown in generation formula (II) in the presence of cuprous bromide and potassium tert-butoxide with trimethylsilanylethyn
The chloro- 6- ethynyl pyridines of N- cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one；
2) compound N shown in formula (II) obtained step 1)-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- are simultaneously
It is chloro- that [2,3-d] pyrimidine -7 (8H) -one in acidic aqueous solution reclaimed water solution obtains Pa Boxini intermediate N cyclopenta -5- methyl -2-
6- acetylpyridines simultaneously [2,3-d] pyrimidine -7 (8H) -one；
In the case of in the present invention, it is preferred to, the chloro- 6- bromopyridines of N N- cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7
(8H) -one and the mol ratio of trimethylsilanylethyn, cuprous bromide, potassium tert-butoxide are 1：1.2~2.5：0.3~0.6：1.2
~2.
In the case of further preferably, the chloro- 6- bromopyridines of N- cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one
Mol ratio with trimethylsilanylethyn, cuprous bromide, potassium tert-butoxide is 1：1.5~2：0.35~0.5：1.5~1.6.
In the present invention, due to the presence of 2 chlorine, competitive reaction can be formed with bromine when generating the reaction of acetenyl, is
Avoid competing, under preferable case, the condition of step 1) reaction includes：Reaction temperature is 45~50 DEG C, and the solvent of reaction is
THF.Under the conditions of being somebody's turn to do, the reaction of step 1) can be completed for 3~5 hours.
Although the reaction of the present invention can react under household condition, in order to avoid air etc. must influence on reacting, preferably
In the case of, the reaction of step 1) is carried out in the presence of protective gas, and the protective gas is nitrogen, helium or argon gas.
The hydrolysis of step 2) in the present invention, is not particularly limited for acid solution, such as 5~15 weights
Measure % aqueous sulfuric acid.Preferably, the condition of step 2) hydrolysis includes：Reaction temperature is 65~70 DEG C, the catalyst of hydrolysis
For AuCl, AuCl dosage is the chloro- 6- ethynyl pyridines of N- cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one weight
The 6~8% of amount.In the conditions of the invention, the reaction of hydrolysis can be completed for 2~3 hours.
In the present invention, the compound shown in initiation material formula (I) used in the present invention is commercially available or root
It is prepared, such as can be prepared according to the preparation method in WO200832157 or WO2014128588 according to prior art.
In the present invention, the amount of solvent for use is not particularly limited in reaction, can be determined according to actual tests, example
Gross weight as fed intake per 1g adds 1~10ml solvents.
The chloro- 6- acetylpyridines of Pa Boxini intermediate N cyclopenta -5- methyl -2- that method provided by the invention obtains
And [2,3-d] pyrimidine -7 (8H) -one, nucleophilic can occur with 4- (6- amino-pyridine -3- bases)-piperazine -1- carboxylates
Reaction obtains final compound Pa Boxini, and the step may be referred to this area conventional method, such as in CN104910149A
Related manufacturing processes.
Signified room temperature of the invention refers to 25 DEG C ± 5 DEG C.
In the present invention, the conventional method in this area can be used to be monitored tracking to reacting, such as TLC, LCMS,
GCMS etc., reaction finish refer to TLC monitor not excess raw material disappeared or LCMS, GCMS in not excess raw material residue be less than
2%.
Specifically, synthetic route of the invention is as follows：
The invention provides a kind of new way for preparing Pa Boxini, there is provided a kind of Pa Boxini key intermediates N- rings penta
The preparation method of the chloro- 6- acetylpyridines of base -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one, avoids using precious metal
Or poisonous dehydrating agent etc., reaction condition is gentle, and overall yield is also higher, is more suitable for industrialized production.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to explanation the present invention without
It is the further restriction to protection scope of the present invention.
Embodiment 1
A kind of method for preparing Pa Boxini intermediates, this method comprise the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-chloro- 6- bromopyridines of cyclopenta -5- methyl -2- simultaneously [2,3-
D] (8H) the -one 34.3g of pyrimidine -7 (100mmol) deposits in cuprous bromide 5.7g (40mmol) and potassium tert-butoxide 16.8g (150mmol)
Reacted 3 hours for 45~50 DEG C in THF in lower and trimethylsilanylethyn 19.6g (200mmol), after reaction terminates, decompression
Solvent is evaporated off, washes, recrystallizing methanol, compound N-chloro- 6- acetylene of cyclopenta -5- methyl -2- shown in dry formula (II)
Yl pyridines simultaneously [2,3-d] pyrimidine -7 (8H) -one 23.7g, yield 82.4%, purity 99.96% (HPLC area normalization methods).
2) compound N shown in formula (II) obtained step 1)-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- are simultaneously
[2,3-d] pyrimidine -7 (8H) -one 10g is added in acidic aqueous solution (10% aqueous sulfuric acid) and is catalyzed in AuCl 0.7g 7%
Lower 65 DEG C hydrolyze 2 hours, and reaction end is cooled to room temperature, ether extraction, concentrates, washing, recrystallizing methanol, is dried to obtain Pa Bo
Simultaneously [2,3-d] pyrimidine -7 (8H) -one 9.2g, yield are the chloro- 6- acetylpyridines of western Buddhist nun's intermediate N cyclopenta -5- methyl -2-
86.3%, purity 99.98% (HPLC area normalization methods).
Embodiment 2
A kind of method for preparing Pa Boxini intermediates, this method comprise the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-chloro- 6- bromopyridines of cyclopenta -5- methyl -2- simultaneously [2,3-
D] (8H) the -one 34.3g of pyrimidine -7 (100mmol) exists in cuprous bromide 5g (35mmol) and potassium tert-butoxide 17.9g (160mmol)
Lower and trimethylsilanylethyn 14.7g (150mmol) reacts 4 hours for 65 DEG C in THF, after reaction terminates, removes under reduced pressure molten
Agent, washing, recrystallizing methanol, compound N-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- shown in dry formula (II)
And [2,3-d] pyrimidine -7 (8H) -one 23.4g, yield 81.3%, purity 99.95% (HPLC area normalization methods).
2) compound N shown in formula (II) obtained step 1)-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- are simultaneously
[2,3-d] pyrimidine -7 (8H) -one 10g is added in acidic aqueous solution (15% aqueous sulfuric acid) to be catalyzed in AuCl 0.6g (6%)
Lower 70 DEG C hydrolyze 3 hours, and reaction end is cooled to room temperature, ether extraction, concentrates, washing, recrystallizing methanol, is dried to obtain Pa Bo
Simultaneously [2,3-d] pyrimidine -7 (8H) -one 9.2g, yield are the chloro- 6- acetylpyridines of western Buddhist nun's intermediate N cyclopenta -5- methyl -2-
87.2%, purity 99.91% (HPLC area normalization methods).
Embodiment 3
A kind of method for preparing Pa Boxini intermediates, this method comprise the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-chloro- 6- bromopyridines of cyclopenta -5- methyl -2- simultaneously [2,3-
D] (8H) the -one 34.3g of pyrimidine -7 (100mmol) deposits in cuprous bromide 7.2g (50mmol) and potassium tert-butoxide 17.9g (160mmol)
React 3 hours for 60 DEG C in THF in lower and trimethylsilanylethyn 19.6g (200mmol), after reaction terminates, remove under reduced pressure
Solvent, washing, recrystallizing methanol, compound N-chloro- 6- acetenyls pyrroles of cyclopenta -5- methyl -2- shown in dry formula (II)
Pyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one 22.9g, yield 79.6%, purity 99.91% (HPLC area normalization methods).
2) compound N shown in formula (II) obtained step 1)-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- are simultaneously
[2,3-d] pyrimidine -7 (8H) -one 10g is added in acidic aqueous solution (10% aqueous sulfuric acid) to be catalyzed in AuCl 0.8g (8%)
Lower 70 DEG C hydrolyze 3 hours, and reaction end is cooled to room temperature, ether extraction, concentrates, washing, recrystallizing methanol, is dried to obtain Pa Bo
Simultaneously [2,3-d] pyrimidine -7 (8H) -one 9.2g, yield are the chloro- 6- acetylpyridines of western Buddhist nun's intermediate N cyclopenta -5- methyl -2-
86.5%, purity 99.91% (HPLC area normalization methods).
Embodiment 4
A kind of method for preparing Pa Boxini intermediates, this method comprise the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-chloro- 6- bromopyridines of cyclopenta -5- methyl -2- simultaneously [2,3-
D] (8H) the -one 34.3g of pyrimidine -7 (100mmol) deposits in cuprous bromide 4.3g (30mmol) and potassium tert-butoxide 22.4g (200mmol)
Reacted 4.5 hours for 55 DEG C in THF in lower and trimethylsilanylethyn 24.6g (250mmol), after reaction terminates, decompression is steamed
Except solvent, washing, recrystallizing methanol, compound N-chloro- 6- acetenyls of cyclopenta -5- methyl -2- shown in dry formula (II)
Pyrido [2,3-d] pyrimidine -7 (8H) -one 21.9g, yield 76.1%, purity 99.78% (HPLC area normalization methods).
2) compound N shown in formula (II) obtained step 1)-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- are simultaneously
[2,3-d] pyrimidine -7 (8H) -one 10g is added in acidic aqueous solution (5% aqueous sulfuric acid) to be catalyzed in AuCl 0.5g (5%)
Lower 65 DEG C hydrolyze 3.5 hours, and reaction end is cooled to room temperature, ether extraction, concentrates, washing, recrystallizing methanol, is dried to obtain pa
The chloro- 6- acetylpyridines of Bo Xini intermediate N cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one 8.9g, yield
For 84.2%, purity 99.84% (HPLC area normalization methods).
Embodiment 5
A kind of method for preparing Pa Boxini intermediates, this method comprise the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-chloro- 6- bromopyridines of cyclopenta -5- methyl -2- simultaneously [2,3-
D] (8H) the -one 34.3g of pyrimidine -7 (100mmol) deposits in cuprous bromide 8.6g (60mmol) and potassium tert-butoxide 13.5g (120mmol)
React 3.5 hours for 65 DEG C in THF in lower and trimethylsilanylethyn 6.1g (120mmol), after reaction terminates, remove under reduced pressure
Solvent, washing, recrystallizing methanol, compound N-chloro- 6- acetenyls pyrroles of cyclopenta -5- methyl -2- shown in dry formula (II)
Pyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one 22.1g, yield 76.6%, purity 99.81% (HPLC area normalization methods).
2) compound N shown in formula (II) obtained step 1)-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- are simultaneously
[2,3-d] pyrimidine -7 (8H) -one 10g is added in acidic aqueous solution (10% aqueous sulfuric acid) to be catalyzed in AuCl 1g (10%)
Lower 60 DEG C hydrolyze 3.5 hours, and reaction end is cooled to room temperature, ether extraction, concentrates, washing, recrystallizing methanol, is dried to obtain pa
The chloro- 6- acetylpyridines of Bo Xini intermediate N cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one 9.1g, yield
For 85.7%, purity 99.79% (HPLC area normalization methods).
Embodiment 6
Such as the preparation method of the Pa Boxini intermediates in embodiment 1, except that, in step 2), do not make AuCl,
Obtain the chloro- 6- acetylpyridines of Pa Boxini intermediate N cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one
11.0g, yield 53.2%, purity 87.91% (HPLC area normalization methods).
Comparative example 1
Such as the preparation method of the Pa Boxini intermediates in embodiment 1, except that, in step 1), without using bromine
Change cuprous, obtain compound N-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- shown in formula (II) simultaneously [2,3-d] pyrimidine -7
(8H) -one 15.6g, yield 54.2%, purity 96.46% (HPLC area normalization methods)
Comparative example 2
Such as the preparation method of the Pa Boxini intermediates in embodiment 1, except that, in step 1), without using bromine
Change cuprous and potassium tert-butoxide, obtain compound N-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- shown in formula (II) simultaneously [2,3-
D] pyrimidine -7 (8H) -one 4.8g, yield 16.4%.
Comparative example 3
Such as the preparation method of the Pa Boxini intermediates in embodiment 1, except that, in step 1), use is identical
The potassium carbonate of mole substitutes potassium tert-butoxide, obtains compound N-chloro- 6- acetenyls of cyclopenta -5- methyl -2- shown in formula (II)
Pyrido [2,3-d] pyrimidine -7 (8H) -one 17.8g, yield 61.9%, purity 98.70% (HPLC area normalization methods).
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.In addition, any group can also be carried out between a variety of embodiments of the present invention
Close, as long as it without prejudice to the thought of the present invention, it should equally be considered as content disclosed in this invention.
Claims (3)
- A kind of 1. method for preparing Pa Boxini intermediates, it is characterised in that this method comprises the following steps：1) by the compound N shown in formula (I)-chloro- 6- bromopyridines of cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one In the presence of cuprous bromide and potassium tert-butoxide the compound N-ring penta generated shown in formula (II) is reacted with trimethylsilanylethyn The chloro- 6- ethynyl pyridines of base -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 (8H) -one；The chloro- 6- bromines pyrroles of N- cyclopenta -5- methyl -2- Simultaneously [2,3-d] pyrimidine -7 (8H) -one and the mol ratio of trimethylsilanylethyn, cuprous bromide, potassium tert-butoxide are 1 for pyridine：1.2~ 2.5：0.3~0.6：1.2~2；Step 1) reaction condition be：Reaction temperature is 45~50 DEG C, and the solvent of reaction is THF；2) compound N shown in formula (II) obtained step 1)-chloro- 6- ethynyl pyridines of cyclopenta -5- methyl -2- simultaneously [2, 3-d] (8H) -one of pyrimidine -7 obtains the chloro- 6- of Pa Boxini intermediate N cyclopenta -5- methyl -2- in acidic aqueous solution reclaimed water solution Acetylpyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one；Step 2) hydrolysis condition be：Reaction temperature is 65~70 DEG C, hydrolysis Catalyst is AuCl, and AuCl dosage is the chloro- 6- ethynyl pyridines of N- cyclopenta -5- methyl -2- simultaneously [2,3-d] pyrimidine -7 The 6~8% of (8H) -one weight；
- 2. according to the method for claim 1, it is characterised in that the chloro- 6- bromopyridines of N- cyclopenta -5- methyl -2- simultaneously [2,3- D] (8H) -one of pyrimidine -7 and trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide be 1：1.5~2：0.35~ 0.5：1.5~1.6.
- 3. according to the method described in claim 1 or 2, it is characterised in that the reaction of step 1) exists in protective gas, institute It is nitrogen, helium or argon gas to state protective gas.
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| CN105294681A (en) * | 2014-07-26 | 2016-02-03 | 广东东阳光药业有限公司 | CDK small-molecule inhibitor compounds and application therefore |
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| CN104892604A (en) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor |
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| Design, Synthesis, and Evaluation in Vitro of Quinoline-8-carboxamides, a New Class of Poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) Inhibitor;Anna-Marie Lord et al.;《J. Med. Chem.》;20081231;第52卷(第3期);868-877 * |
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